Ji Kim PS3 May 7, 2010. Objective Describe the association between corticosterids/...
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Transcript of Ji Kim PS3 May 7, 2010. Objective Describe the association between corticosterids/...
Ji Kim PS3May 7, 2010
ObjectiveDescribe the association between corticosterids/
immunosuppressions and PTDM
Explain the treatments of PTDMOral agents: biguanides, sulfonylureas,
meglitinides, thiazolidinedionesInsulin
Introduction to Diabetes MellitusDiabetes mellitus (DM)- a syndrome that is caused by a
relative or absolute lack of insulin.
Glycated hemoglobin (A1C) is a form of hemoglobin used primarily to identify the average plasma glucose concentration over prolonged periods of time. A1C goal <7%
Normoglycemia
IFG or IGT (Pre-diabetes)
DM
FPG < 100 mg/dl
FPG 100 – 125 mg/dl (IFG)
FPG ≥ 126 mg/dl
2-h PG < 140 mg/dl
2-h PG 140 – 199 mg/dl (IGT)
2-h PG ≥ 200 mg/dlSymptoms of DM and randomplasma glucose ≥ 200 mg/dl
ADA guideline
Insulin- made from beta cells of pancreatic islets of Langerhans
PTDM incidence and risk factors In the 12 studies of kidney transplantation, incidence of PTDM estimates ranged from to 2 to 50%.
Immunosuppression regimen explained 74% of the variability in the 12 months cumulative incidence (P =0.0004). (Victor M. Montori et al 2002)
Risk factors
Preexisting Transplant Associated
NonmodifiableAgeGenderRace/ethnicityFamily history
Potentially modifiableObesityPhysical inactivityHepatitis C
NonmodifiableInherited and acquired defects in insulin sensitivity
Potentially modifiableWeight gainGlucocorticoidsCalcineurin inhibitorsSirolimus
Kasiske BL et al. 2001
What is PTDM?PTDM has emerged as a major adverse effect of
immunosuppressive drugs.Corticosteroids
Affects glucose metabolism by increasing hepatic glucose production and by reducing peripheral tissue insulin sensitivity
Related to the dose and the duration of therapy
Calcineurin inhibitor (cyclosporine, tacrolimus ) Predominantly by impairimng beta cell insulin Tacrolimus is concentrated in the pancreas and it may
inhibit pancreatic insulin secretion.
mTOR inhibitor (sirolimus) Long-term mTOR inhibition impairs activation of IRS-1
and AKT and augments insulin resistance and β cell dysfunction
Goldberg et al. 2007 & Pavlakis et al. 2008
PATIENT: JR34 yo male with a PMH of severe aplastic anemia, status
post unrelated donor stem cell transplant on July 2004
PMH: Chronic GVHD involving the mouth, eyes, liver, and skinCellulitis of the footStatus post spelenectomy HTN HyperlipidemiaNo hx of DM
Admitted on April 13, 2010, for the lesion in the left foot with blisters
Notable Medications Prior to admission
Prednisone 20mg PO every other day Sirolimus 1mg PO every other day Tacrolimus 1mg PO two times a day
Admission Zosyn 3.375g IV Q 6 h Levofloxacin 750mg/150ml Bag IV QPM
LABS Prior to Admission
2/7/09 Glu level= 167 (↑ ) 2/28/10 Glu level= 191 (↑ ) 3/2/10 Glucose level= 168 (↑ )
Admission 4/13/10 Glucose level= 237 (↑ ) 4/14/10 Glucose level=180 (↑ )
Ht=5’6”, Wt=50kg, Scr=1.06 (4/14) IBW= 63.8kg, CrCL= 69 ml/min
PTDM has been clearly associated with an elevated risk for serious infections, acute graft rejection, and even death.
As diabetes has a negative impact on patient and graft outcome, the transplant practitioner must be cautious in screening and managing diabetes after transplantation.
Let’s focus on the therapeutic management of PTDM!!
Therapeutic management of DM
Biguanides
Generic name (trade)
Total dose (mg/interval)
MOA Comments
Metformin (Glucophage)
500-850mg BID/TID
•↓ hepatic glucose output (Primary)
•↓ insulin resistance in periphery (secondary)
•↓ or delayed absorption of carbohydrates
•First line treatment in Type 2 patients
•Lactic acidosis (rare)
•Major CI is renal (Scr>1.4 females and Scr>1.5 males)
•Iodinated IV radiocontrast dye
Sulfonyureas
Generic name (trade)
Total dose (mg/interval)
MOA Comments
Glipizide (Glucotrol)
Glyburide (Micronase/Diabeta)
Glimepiride (Amaryl)
2.5-20mg QD/BID
2.5-10mg QD/BID
1-8mg QD
•↑ Insulin secretion from the Beta cells of pancreas
•↓ insulin resistance
•↓ hepatic glucose output
•Hypoglycemia particularly with renal dysfunction
•Use cautiously in elderly and those with ↓ renal function
•Start at the low and end of the dosing range
•Increase the dose every one or two weeks until maximum doses are achieved
•DDI with Beta-blockers: ↑ hypoglycemic effect
Meglitinides
Generic name (trade)
Total dose(mg/interval)
MOA Comments
Repaglinide (Prandin)Natgeglinide (Starlix)
0.5-4mg TID
60-120mg TID
↑ Insulin secretion from Beta cells of pancreas
•Hypoglycemia particularly with renal dysfunction
•Take only with meals. Skip dose if meal is skipped. (Good for patients who eat irregularly)
•Major difference vs. Sulfonylureas: Short acting & target PPG levels
• If no response from sulfonylurea, don’t switch to a meglitinide.
ThiazolidinedionesGeneric name (trade)
Total dose (mg/interval)
MOA Comments
Rosiglitazone (Avandia)
Pioglitazone (Actos)
4-8mg QD/BID
15-45mg QD
•↑ insulin sensitivity at the muscle by acting as an agonist on the peroxisome proliferator activated receptor gamma which results in increased glucose uptake (Primary)
•↓ Hepatic glucose production (Secondary)
•Indications for use include monotherapy, combined with metformin, sulfonuylureas, and insulin
•↓ insulin requirements and improve control
•Can be used in renal failure
•Slow onset (Onset at 3 weeks; max 4-8 wks)
•No hypoglycemia
•Weight gain
• Use cautiously in pts with edema and heart failure
•Monitor liver function test
PTDM in Hospital settingInsulin treatment is generally preferred
Superior predictability and rapid titratability Control hepatic glucose production Basal insulin preparation (intermediate/long-
acting) between mealsBolus insulin (rapid/short-acting) to control
postprandial elevations of blood glucoseUse sliding scale insulin to “Start low and go
slow”Fail PO agents -> add basal insulin -> add
bolus insulin
Inzucchi SE. et al. 2006
Oral agents can safely be used in medically stable patients Metformin is best AVOIDED due to
contraindications Renal/hepatic impairement, HF, pending radiology
studies involving IV contrastSulfonylureas are most often used.
Effective, low cost, average ↓blood glucose by 20%, ↓A1c 1.1-1.9%
Shorter-acting meglitinides provide a reasonable inpatient alternative
TZDs generally safe , but delayed onset of action (days to weeks), limiting their clinical utility
Del Prato S. et al. 2006
Thiazolidinediones (TZDs) PROS:
Not metabolized by the CYP3A4 system, lowering the risk for dangerous interactions with CNIs
Baldwin and Duffin et al. (2004) ↓ A1c 8.1% to 6.7% (P=0.01) in 18 posttransplant pts with rosi
and insulin/sulfonylurea Voltouch et al. (2005)
4 weeks rosiglitazone treatment (8mg/d) Improves insulin sensitivity Significant decline in fasting and 2 h plasma glucose (from 6.4
to 5.8 mmol/l, P = 0.01 and from 14.2 to 10.6 mmol/l, P = 0.03
CONS: Nissen SE et al. (2007)
↑ risk of MI and borderline increase in the risk of cardiovascular death
CONTROVERSY?
Back to the Case, JRDate Glucose
Level(mg/dL)
Treatments
4/16/10 266 (↑ ) • Start Glipizide XL 5mg PO daily (4/16-4/20)
• Use Accu-check QAC, QHS
4/17/10 218-426 (↑ ↑)
Start Insulin Sliding scale
4/20 /10
172 (↑ ) •Blood sugar elevated while patient is on prednisone
•Switch to glyburide 5mg before breakfast when he is on prednisone 20mg (4/21-4/26)
•Only use glyburide 2.5mg daily for the days when he is not on prednisone (4/22- 4/27)
•Humalog sliding scale using 2 units for each increment of 50mg/dl of blood glucose greater than 150mg/dl AC and HS
Glipizide XL vs. GlyburideBoth 2nd generation sulfonyureasGlipizide XL
Initial dose 5mg daily; increase by 5mg q 1-2 weeksDuration: 24 hours Absorption: Rapid and complete
GlyburideDose: 1.25-20mg/d QD or BIDOnset of action: Serum insulin levels begin to
increase 15-60 minutes after a single dose Duration: ≤24 hours Absorption: Significant within 1 hour
Date Glucose Level (mg/dL)
Treatments
4/25/10 268 (↑ ) Increase to glyburide 10mg after breakfast and 5mg before dinner every other day (4/25–4/29)Change prednisone 20mg dailyHold insulin sliding scale
4/27/10 60 (↓) Felt sweaty and shaky-> orange juiceHold glyburide Continue Humalog sliding scale (4/27- present)
5/1/10 312 (↑ ) Switch to glimepiride 1mg PO every other day (5/1-5/2)
5/2/10 164 (↑ ) Increase to glimepiride 2mg PO every other day (5/3 to 5/4)
5/3/10 332 (↑)
5/4/10 150 (↑) Increase to glimepiride 4mg PO every other day (5/4 to present)
Glyburide vs. GlimepirideGlyburide
2nd generation of sulfonyureas
Glimepiride3rd generation of sulfonyureasMild reduction in insulin resistanceLess hypoglycemic effectsSafe in patients with advanced kidney diseaseDose: 1-4mg once daily; after a dose of 2mg once
daily, increase in increments of 2mg at 1 to 2 week intervals
Maximum dose 8mg once daily
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15 ThuApr 2010
22 Thu 1 May
Glucose, POC (Whole Blood)mG
/dL
ROMERO, JOSE
Glucose, POC (Whole Blood) (mG/dL)4/17 Initiate insulin
4/27 Hypoglycemia
5/1 Switch to Glimepiride4/20
Switch to glyburide
Alternative Immunosuppressive treatments?Both calcineurin inhibitors alter insulin secretion
Effects of tacrolimus seem to be more profound and intense compared with the CsA-induced ones
Tacrolimus specific binding protein, i.e. FKBP-12, is preferentially located in beta cells, leading to a strong concentration of the drug in these cells
CsA specific binding site (ciclophiline) is preferentially located in the heart, the liver and kidneys.
Higher incidence in tacrolimus1. Woodward RS, et al. (2003)
In the 6-month, open-label, randomized, prospective multicenter DIRECT study
Tacrolimus and CsA were compared in 567 non-diabetic kidney graft recipents
PTDM or new IFG occurred in 26% of CsA and 33.6% in tacrolimus (P=0.046)
2. Heisel O, et al. (2004) Meta-analysis of 56 prospective and randomised
clinical trials 16.6% with tacrolimus vs. 9.8% with CsA, without
any difference according to the transplanted organ
FK/MTX vs. CsA/MTX as GVHDYagasaki H. et al. 2009
Patients with severe aplastic anemia (SAA) given unrelated donor BMT
47 pairs matched exactly for recipient age & conditioning regimens
45 patients achieved engraftment in FK & 42 patient in CsA
Results FK/MTX CsA/MTX P value
Grade II-IV acute GVHD
28.9% 32.6% 0.558
Chronic GVHD
13.3% 36% 0.104
5-year survival
82.8% 49.5% 0.012
SirolimusSirolimus is a potent immunosuppresant1.Johnson RW et al.(2001) and Kreis H et al. (2000)
NODM rates were not reduced in sirolimus treated patients
2.Romagnoli J et al. (2006) Combination CsA and sirolimus has been associated
with more NODM than CsA alone
3.Teutonico A et al. (2005) Decreases in insulin sensitivity, pancreatice cell
function, and overall glucose tolerance have been demostrated, either after conversion from CsA to sirolimus or after tacrolimus elimination from a combined tacrolimus/sirolimus regimen
Effect of corticosteroid-sparing regimen on PTDMChronic high-dose steroid therapy was a
major contributing factor to the development of PTDM.
Boots et al. (2002)62 patients treated with tacrolimus were
prospectively randomized to stop Prednisone 10mg after day 7 posttransplantation (STOP) or to gradually taper steroids in 3-6months (TAP)
Follow up of2.7 yearsIncidence of PTDM
STOP 8% and TAP 30.3% (p=0.04)
Back to the Case, JRJR is on prednisone, tacrolimus, and sirolimus
since August 2004City of Hope protocol for GVHD patientsSo many options: making the right choice for JR?
May 5, 2010Glu= 206 @13:23 (↑ )JR is on glimepiride 4mg PO every other day,
insulin sliding scale, prednisone, tacrolimus, sirolimus
His blood sugar is still uncontrolled, continue following the same regimen?
My recommendationIf inadequate response to maximal dose (8mg), then
combination therapy with TZDs may be considered.
Insulin therapyTraditional basal-bolus insulin regimens, such as
glargine/detemir insulin combined with rapid-acting, may be considered.
Tailoring immunossupressionConversion to cyclosporine may be considered.
Therapeutic lifestyle modificationsDiet-limited intake of calories, carbohydrates, and
saturated fatsExercise-aerobic activity, resistance training
ConclusionPTDM results from impaired insulin secretion
and peripheral insulin resistance, largely generated by chronic immunosuppression.
In trasplanted patients, hyperglycemia is associated with an increased risk for cardiovascular disease, serious infections, graft rejection, and even death.
PTDM should be treated in a comprehensive and aggressive manner.
THANK YOU!!!
Any Questions???